The NF-KB/lKBalpha system is an essential cell signaling system and is representative of a family of protein-protein interactions in the cell. The function of this system provides a challenge to the main structure-function paradigm in biophysics because parts of both partners are incompletely structured when the molecules are isolated. Thus there are major implications for many areas of proteomics, which also involve natively unfolded proteins. Specific recognition of IKBalpha by NF-KB involves collaborative folding and binding between the two proteins. We will investigate computationally the kinetics of this process, because this collaborative folding/binding event may be an example of the proposed "fly-casting mechanism" previously suggested by us as a possible reason for utilization of unfolded proteins in biological systems. These studies will combine energy landscape theory with simulations using a variety of model energy functions. This system is a particularly auspicious choice for such a study because a very extensive model of the in vivo kinetics has already been established and tested in the Hoffmann laboratory. Thus the evolutionary and functional significance of "fly-casting" can be assessed. Our theoretical predictions will be tested by laboratory investigations of the Ghosh, Komives and Dyson groups. The collaborative folding/binding found here raises more general issues concerned with experimental and theoretical characterization of the structure of proteins with dispersed ensembles of structures. Developing computer algorithms for dealing with this circumstance, based on replica methods and energy landscape theories, is another focus of our theoretical work. Developing approaches to predict binding modes for such floppy proteins using sequence information alone is another goal. Finally the basic biophysics that drives the association of partially folded partners will be addressed using the simulation models we generate. Studying the underlying forces in molecular detail may give insight into the specificity patterns exhibited by this family of proteins, which participate in many different signaling events relevant to physiological responses. The NF-KB/lKBalpha system has been implicated in several diseases ranging from osteoporosis to septic shock. Controlling folding/binding in this system may provide a new strategy for drug intervention, although our emphasis is on the basic science of the problem.